This invention relates to novel esters of hydroxyl-containing indolocarbazoles and acids containing selected solubilizing groups, to compositions including the indolocarbazole esters and to methods for the use of the indolocarbazole esters in the elucidation and understanding of certain diseases, including diseases of the prostate.
Indolocarbazoles are a well-known class of small molecules. In animal studies, activity of indolocarbazoles as therapeutic agents in the treatment of pathological disorders of the prostate have been demonstrated. Additionally, indolocarbazoles are useful as inhibitors of protein kinases C, A and G, myosin light chain kinase, and trk, a tyrosine kinase activated by neurotrophins. Indolocarbazoles have been also shown to be active neurologic agents.
U.S. Pat. No. 4,877,776 describes indolocarbazole derivatives which exhibit protein kinase C-inhibiting activity. U.S. Pat. No. 4,923,986 and PCT patent specification WO94/02488 describe physiologically-active indolocarbazole derivatives having anti-tumor activities. PCT patent specification WO94/27982 describes the use of indolocarbazole derivatives to treat a pathological condition of the prostate gland in a mammal. Japanese Patent Specification JP63-295588 describes indolocarbazole derivatives which are inhibitors of protein kinase C. PCT patent specification WO93/08809 describes indolocarbazole derivatives which potentiate neurotrophic activity. PCT patent specification WO94/06799 describes indolocarbazole derivatives as therapeutic agents for thrombocytopenia.
A significant problem which has limited the usefulness of indolocarbazoles as therapeutic and research reagents is their poor solubility in aqueous solutions. In light of the significant useful activities of indolocarbazoles, there is a need for novel indolocarbazole derivatives which achieve the beneficial effects of indolocarbazoles and which have increased aqueous solubility. Such compounds would allow for in vivo delivery of indolocarbazole-containing solutions without creating additional problems for the recipient. This invention is directed to this important end.
The present invention provides novel soluble esters of hydroxyl-containing indolocarbazoles. The subject invention also includes compositions including the indolocarbazole esters, and methods for the use of the indolocarbazole esters in the treatment of diseases, including pathological conditions of the prostate gland.
In one aspect, compounds are provided having the formula Qxe2x80x94Lxe2x80x94C(xe2x95x90O)xe2x80x94A wherein A is a solubilizing group, L is oxygen and Q is an indolocarbazole residue of Formula I: 
Constituent members are defined infra, as well as preferred constituent members.
The compounds of the invention are useful in a variety of applications. For example, the compounds may be employed in research applications to understand, for example, the mechanistic aspect of the therapeutic benefits derived therefrom, i.e., in the exploitation of scientific understanding of how these small molecules effectuate a positive result on certain cancerous tumors. Additionally, particularly preferred compounds of the invention can be utilized as a screening tool to discover other small molecules which offer equivalent efficacious results in in vitro and in vivo models of disease states of interest.
In a clinical setting, compositions comprising the claimed compounds are preferably used as therapeutics for treating a pathological condition of the prostate gland, e.g., benign prostatic hypertrophy or prostate cancer; compositions comprising the claimed invention are also useful as therapeutics for the treatment of neurological diseases.
These and other features of the compounds will be set forth in expanded form as the disclosure continues.